Aralkyl piperazines and salts thereof



3,322,768 ARALKYL PIPERAZHNES AND SALTS THEREOF Manfred Schorr, Rudolf Fussgiinger, and Georg Nesemann, Frankfurt am Main, and Fritz Bauer, Bad Soden, Taunus, Germany, assignors to Farbwerlke Hoechst Aktiengesellschaft vormals Meister Lucius & Eriining, Frankfurt am Main, Germany, a corporation of Germany No Drawing. Filed July 13, 1965, Ser. No. 471,731 Claims priority, application Germany, Dec. 28, 1959, v 184 6 Claims. (of. 260-268) This application is a continuation-in-part of US. patent application Ser. No. 77,021 filed Dec. 20, 1960 and now abandoned.

The present invention relates to piperazines of the Formula I to the physiologically compatible acid addition salts thereof and to their quaternary salts in which the cations are of the formulae 11a and 11b in which R is hydrogen, halophenyl or halobenzyl, R R and R are hydrogen or halophenyl, A is hydrogen or lower alkyl, R, is alkyl of 1 to 4 carbon atoms, hydroxyalkyl of 1 to 4 carbon atoms or dialkylaminoalkyl, the alkyl groups of which have 1 to 4 carbon atoms, R is hydrogen or alkyl of 1 to 4 carbon atoms, or R and R together with the nitrogen atom form a piperidino or N-methyl-piperazino ring.

These compounds are characterized particularly by the facts that (a) the 4-nitrogen atom of the piperazine ring carries a chain of three carbon atoms identified herein as the ,6 and gamma carbon atoms, (b) the :x-carbon atom is always unsubstituted, (c) they contain a total of at least two halophenyl groups, i.e., at least two of R R and R are halophenyl when R is hydrogen and at least one of R R and R is halophenyl when R is halophenyl or halobenzyl, and (d) they do not contain any unsubstituted phenyl groups.

The products of the present invention are novel compounds exhibiting Valuable therapeutic properties, above all bacteriostatic, bactericidal, fungistatic and fungicidal properties.

This invention further relates to a process of preparing the new piperazines of the Formula I by reacting a primary amine of the Formula III in which R, R R R and A have the meanings given above, with alkyl-bis-(Z-halogeno-ethyl)amines of the Formula IV 3,322,768 Patented May 30, 1967 in which R, vhas the meaning given above and Hal stands for a halogen atom, or by causing amines of the Formula VI or VII (VII) to act on a bis-(Z-halogeno-ethyl)-amine of the Formula V or a salt thereof obtainable by starting from a primary amine of the Formula III and, if desired, converting the piperazine obtained into the corresponding acid addition salts by treatment with physiologically compatible inorganic acids or into monoquaternary salts by treatment with alkylating agents.

The terms halophenyl and halobenzyl stand for phenyl and benzyl groups being substituted by one or two halogen atoms in the phenyl nucleus. As halogen atoms especially chlorine enters into consideration as substitucut.

The following radicals may be mentioned as examples: 2-, 3-, and 4-chlorophenyl, 2-, 3-, and 4-chlorobenzyl and the corresponding fluorine or bromine derivatives, 2,3-, 2,4-, 2,5-, 3,4 and 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 3,4-, and 3,5-dichlorobenzyl and the corresponding bromine derivatives; 4-fiuorophenyl and 4-fiuorobenzyl.

The substituent R may for example represent methyl, ethyl N-propyl, isopropyl, n-butyl, sec. butyl and tert. butyl groups. As alkyl groups R there may likewise be used the above mentioned substituents, preferably methyl or ethyl groups.

As starting substances for the process according to the present invention, the following primary amines of the Formula III enter into consideration, for example:

Byy-bls- (4-chlorophenyl) -propylamine,

B-(4'chlorophenyl) -(2,4-dichlorophenyl) -propylamine,

fi- 3 ,4-dichlorophenyl -'y- (4-chlorophenyl -p1'o pylamine,

,B-y-bis-( 3,4-dichlorophenyl) -propylamine,

'y,'y-bis- (4-chlorophenyl -propylamine,

18, -bis-(2,4-dichlorophenyl)-propylamine,

3,/3-bis- 4-chlorobenzyl -propylamine,

18,,8-bis- 3 ,4-dichlorobenzyl -propylamine,

[8,[3-bis- 2,4-dichlorobenzyl -propylamine,

,8- (4-chlorobenzyl) w- (4-chlorophenyl -propylamine,

,8- (3 ,4-dichlorobenzyl) -'y- (3 ,4-clichlorophenyl propylamine,

8- (4-chlorophenyl) -'y- (4-fluorophenyl) -propylamine,

13-(4-chlorophenyl)-'y-(4-bromophenyl) -propylamine,

,'y,' -tri-(4-chloropheny1) -propylamine,

'y 3-chlorophenyl) -'y,'y-hiS (4-chlorophenyl) -propylamine,

J 'y,'y-bis (4-fluorophenyl) -'y- (4-chlorophenyl) -propyl amine, i 'y- 3 ,4-dichlorophenyl 'y,'y-bis- (4-chlorophenyl) -propylamine, 'y- (3 ,4-dichlorophenyl) -'y- (4-chlorophenyl) -propylamine.

Furthermore, there can be used as starting substances the corresponding amines substituted at the nitrogen atom by two halogenoethyl groups.

The compounds mentioned as starting substances, as far as primary amines are concerned, may, for example, be prepared by hydrogenation of the corresponding nitriles whereas the corresponding amines substituted at the nitrogen atom by two halogenoethyl groups can be obtained from the first mentioned primary amines. To this purpose, the primary amines mentioned above can, for example, be reacted with ethylene oxide in an inert solvent, such as benzene, at elevated temperatures preferably between 80 and 160 C., or with ethylene chlorohydrin in the presence of an acid-binding agent, for example calcium oxide, at temperatures between 80 and 160 C. There are thus formed the corresponding bis-(fl-hydro-xyethyl)-amines the hydroxy groups of which can be replaced by halogen atoms by reaction with halogenating agents, such as phosphorous acid halides, phosphoric acid halides or thionyl chloride in the presence of an inert solvent, for example of a chlorinated hydrocarbon such as chloroform. The reaction of a bis-(fl-hydroxyethyD- amine with an excess amount of thionyl chloride is of particular advantage. After evaporation of the solvent and of the chlorinating agent in excess there is obtained the hydrochloride of the bis-(B-chlo-rethyl)-amine which can be used for further reaction without isolation of the free bases.

According to the process of the present invention a primary amine of the Formula III can, for example, favorably be reacted with an alkyl-bis-(fl-halogenoethyl)- amine of the Formula IV. The operation is advantageously carried out in the presence of a solvent or diluent, for example lower aliphatic alcohols, such as methanol or ethanol. For binding the hydrogen halide set free during the reaction there is suitably added an acid-binding agent. For this purpose there are suitable, for example, alkali metal carbonates, alkali metal bicarbonates or tertiary amines such as pyridine or triethyl amine. The alkyl-bis- (fi-halogenoethyD-amine serving as the reaction component of the primary amine may be used in the form of the free base as well as in the form of a corresponding salt, for instance the hydrochloride. In the latter case the basic compound has to be added in a bimolar excess. The temperatures required for the reaction vary according to the nature of the starting substances and the solvents used. In order to accelerate the reaction it is of advantage to operate at raised temperatures, for example, between 80 and 160 C. The reaction can be carried out in an open vessel as well as in an autoclave. For processing, the reaction mixture is made alkaline by adding bases, such as sodium hydroxide solution, and the piperazines formed during the reaction are extracted by means of suitable organic solvent. Since, as a rule, the free piperazines cannot be distilled without decomposition, it is of advantage to purify them by conversion into a corresponding acid addition salt, preferably into the corresponding hydrochlorides.

According to a further feature of the present invention, an amine of the above-mentioned Formula III may first be converted into a corresponding bis-(fi-halogenoethyD- amine. Amines of the Formula VI may then be reacted with the reaction product obtained, which if necessary, may be used in the form of a corresponding salt. This reaction and processing can be carried out in the abovedescribed manner. For binding the hydrogen halide set free there is preferably used according to this procedure an excess of the amine of the Formula VI participating in the reaction.

The piperazines obtained are generally very viscous, yellow oils only distillable with decomposition. They can be transformed into the corresponding salts by means of inorganic or organic acids. It has already been mentioned that the transformation of the free bases into the corresponding salts can advantageously be used for purification and isolation of the products from the reaction mixture. The salt formation can take place at one or at both basic nitrogen atoms. Generally, the salts obtained by reaction with 2 equivalents of an acid crystallize well and, according to the nature of the anions and of the radicals R they dissolve more or less easily in water.

For conversion of the piperazines into corresponding acid addition salts there may, for example, be used the following acids: inorganic acids, for instance, hydrohalic acids such as hydrochloric acid or hydrobromic acid, or sulfuric acid, phosphoric acid, amidosulfonie acid. As organic acids there are suitable, for example: acetic acid, propionic acid, butyric acid, stearic acid, oxalic acid, tartaric acid, malic acid, succinic acid, fumaric acid, maleic acid, citric acid, aspartic acid, aceturic acid, salicylic acid, para-amino-benzoic acid or ethylene-diamine-tetraacctic acid.

Unless they are obtained directly in form of the monoquaternary salts, the piperazines thus formed can be transformed into the corresponding monoquaternization products by treatment with equimolar quantities of a suitable alkylating agent. The use of a solvent or diluent is not absolutely necessary for this reaction but is of advantage in most cases. As diluents there enter, for example, into consideration: hydrocarbons such as benzene, carboxylic acid esters such as ethyl acetate, ketones such as acetone, acyclic or cyclic ethers such as dioxane or tetrahydrofurane or aliphatic alcohols such as methanol or ethanol. The reaction is advantageously carried out at elevated temperatures, preferably Within the range of the boiling point of the solvent used. As al-kylating agents there may be used lower alkyl esters of hydrohalic acids, such as methyl iodide or ethylene chlorohydrin, of sulfonic acids such as para-toluene-sulfonic acid ethyl ester, or of sulfuric acid, for example dimethylor diethyl sulfate. The quaternary compounds crystallize from the reaction solution on cooling or can be obtained in solid form by treatment with suitable solvents, if necessary after previous evaporation of the reaction mixture. Which nitrogen atom is quaternized is not quite certain but the nitrogen atom carrying the radical R is, for steric reasons, more suitable, so that the quaternized products obtained probably consist mainly of salts in whose molecule the radical R is bound to this nitrogen atom.

Surprisingly, the reaction of a bis-(2-halogenoethyl)- amine of the Formula V with amines of the Formula VII does not take place, as could have been expected, with the exchange of one halogen atom each by an amino group but ring closure takes place with formation of monoquaternary piperazinium salts. When using a great excess of the amines of Formula VII the reaction proceeds in the same way. The structure of these piperazinium salts is quite clear; the radicals R and R are bound to the same nitrogen atom. The reaction is carried out in a manner analogous to the reaction with the primary amines of Formula VI.

The monoquaternary piperazinimum salts prepared according to the process of the present invention constitute in most cases crystalline substances which often contain water of crystallization. Most of them are soluble in water, even in the weakly alkaline range. The piperazinium hydroxides on which the salts are based are strong bases.

The compounds of this invention are well tolerated and possess valuable therapeutic properties, above all bacteriostatic, bactericidal, fungistatic or fungicidal activity. In view of these properties the compounds are, for example, suitable as disinfectants in the most varied fields of applieation.

TABLE regulating the osmotic pressure. The pharmaceutical preparations may be prepared by the usual methods. The following examples illustrate the invention; but they are not intended to limit it thereto:

Toxicity (maximum tolerated dose) in mice in mg./2O g. of the compounds a-g a b c d c f g Orally. 25 100 100 25 25 12. 15. 6 subcutaneously 100 4 2 2 5 0.8 12. 5

Lowest eifective concentration causing bactcricidal activity in 7/1111.

after minutes of the compounds a-g a b c d e i g (a) Germs:

Staphylococcus aurcus 32 8 7. 8 15. 6 31.5 02. 5 62. 5

E. coli 1,000 62. 5 02.5 31. 5 125 250 500 B. typhi 250 31.5 62. 5 15.6 31. 5 62.5 31. 5

Streptococcus hcemo1yticus 1. G 0.8 1. 6 1. 6 3 2 2 Staphylococcus aureus 8 0.4 1. 6 0.4 3 2 15. o Cornynebacterium diphthcriae. 4 4 3.1 3 8 4 15. 6 C011 625 15, 6 10.5 31.5 31. 5 62. 5 250 Pseudomonas aeruginosa 2, 500 31. 5 5 31. 5 31.5 62. 5 500 Lowest effective concentration causing iungistatic activity in ylrnl.

(b) Pathogenic yeasts: Candida ulbicans 8 62.5 15. 0 31.5 20 20 (c) Apathogenio molds: Penicilliurn glaucum 20 31. 5 7.8 31.5 40 20 (a) l-hy'droxyethyl-4- ['y,'y,'y-tri- 4-chlorophenyl) EXAMPLE 1 p top Y1] piper azme dlhydrochlonde 40 1 -lJulyl-4-['y,'y,'y-tli(4'-Chl01'0phenyl )-pr0pyl] -piperazine (b) l- (or 4-) methyl- 1 -hydroxyethyl-4- ['yq -tri- (4'- chlorophenyl -propyl] -piperaziniu1n methyl sulfate (0) 1,1-diethy1-4- ['y,'y,'y-trl- (4'-chlorophenyl) -propyl] piperazinimum bicarbonate (d) 1, l -diethy1-4- [fl- 3 ,4'-dichlorobenzyl) -'y (3 ',4'-dichlorophenyl)-propyl]-piperazinium chloride (0) 3 ,8- 3 ',4-dichlorobenzyl -'y- 3 ',4'-dichlorophenyl propyl] -9-methyl-3,6,9-triaza-spiro- [5 ,5] -undecaniu1n chloride (15) 1- (or 4-) methy1-l-butyl-4- [/3-(4'-chlorophenyl) 'y- 2,4'-dichlorophenyl) -propyl] -piperaziniun1 methyl sulfate (g) l-methyl-4- [fl- (4-chlorophenyl -'y- 2',4'-chlorophenyl -propyl] -piperazine dihydrochloride.

The results given in the table show that the products of the present invention show a bacteriostatic action, the

lowest effective concentration being about 0.5v/ml. The

lowest concentration causing a bactericidal action is between about 8-l5' /rnl. The lowest concentration causing a fungistatic action is of about the same order. The tolerability of the products of the invention is likewise excellent as results from the indicated toxicity data.

The compounds may be used as such or in the form of galenic preparations, for example, gelees, powders, ointments, pastes, mixtures that require shaking, tinctures, solutions or suspensions in admixture or conjunction with a pharmaceutical organic or inorganic carrier that does not react with the active ingredient. As carrier substances there may be mentioned, for example, water, gelatine, bolus, lactose, starch, magnesium stearate, talcum, vegetable oils, benzyl alcohol, gums, polyethylene-glycol, cholesterol, white petroleum jelly, zinc oxide, titanium dioxide or other carriers known for medicaments. The prodbilizers, buffers, wetting agents, emulsifiers or salts for 50 grams of N-['y,'y,'y-tri-(4-chlorophenyl)-propyl]-N, N-bis-(ii-chloroethyD-aminc hydrochloride, 250 cc. of a1- cohol and 20 grams of n-butylamine are heated in a shaking autoclave for 5 hours at 120130 C. Most of the solvent is distilled otf, water and sodium hydroxide solution are added to the residue and the base is extracted by means of ether. After drying over potassium carbonate 22 cc. of an alcoholic hydrochloric acid of 30% strength are added to the ethereal solution and the precipitated salt is filtered off with suction. There are obtained 45 grams of l-butyl- 4- ['y,'y,'y-tri- 4-chlorophenyl -propyl] -piperazine dihydrochloride which can be purified by clarification of its solution in isopropanol and preciptation by means of diisopropyl ether. The product melts at 266-268 C. With decomposition. It contains 1 mol of crystal water.

The free l-butyl 4 -tri-(4'-chlorophenyl)-propyl]-piperazine is obtained from the salt by treating it with sodium hydroxide solution and ether, drying and evaporating the ether layer, as a viscous, light-yellow oil.

The N-[y,v,'y-tri-(4-chlorophenyl)-propyl]-N,N-bis-(B- chloroethyl)-amine hydrochloride can, for example, be prepared as follows:

203 grams of 'yqgy-tri-(4-chlorophenyl)-propylamine and cc. of ethylene oxide are dissolved in 600 cc. of benzene and heated in an autoclave for 5 hours at 120 C. After distilling off the solvent there are obtained 250 grams of the crude N-[' ,y-tri-(4-chlorophenyl)-pro ply]-N,N-bis-(,6-hydroxyethyl)-amine in the form of a yellow, very viscous oil that may be directly used for further processing. If the crude amine is dissolved in about double the quantity of diisopropyl ether and the solution is allowed to stand for a prolonged time or is inoculated, crystallization takes place. The amine is obtained as a I colorless crystal powder melting at 109110 C. After re- To a solution of 146 grams of N-[ -tri-(4-chlorophenyl)-propyl]-N,N-bis-(fl-hydroxyethyl)-amine in 300 cc. of chloroform there are added dropwise 145 grams of thionyl chloride, while the temperature is maintained by slight cooling between 10 and 20 C. The reaction mixture is heated for one hour under reflux and the solvent and thionyl chloride in excess are then completely distilled 01f. The viscous brown residue is dissolved in 145 cc. of benzene and 1.5 liters of diethyl ether are added. The product that has separated crystallizes slowly and, after complete crystallization, it can be filtered ofl with suction. There are obtained 105-115 grams of N-[ -tri-(4- chlorophenyl) propyl]-N,N,-bis-(,8-chloroethyl) amine hydrochloride still showing a brown color. By recrystallization from benzene/diisopropyl ether it can be purified; it melts then at 176-l77 C. However, the crude product is also suitable for the further reaction.

EXAMPLE 2 1-(01' 4-) methyl-1-butyl-4-[ -lri-(4-chl0r0phenyl)- propyl]-piperazinium methyl sulfate To a solution of 25 grams of 1-butyl-4-[ -tri-(4- chlorophenyl)-propyl]-piperazine in 100 cc. of benzene there is added dro wise a solution of 6 grams of dimethyl sulfate in 25 cc. of benzene. The reaction mixture is heated for one hour under reflux. After cooling 50 cc. of petroleum ether are added. The quaternary salt crystallizesvery slowly but more rapidly upon inoculation. After filtering off with suction there are obtained 19 grams of l-(or 4-) methyl-1-butyl-4-[ tri (4-chlorophenyl)-propyl]- piperazinium methyl sulfate. The product can further be purified by recrystallization from benzene/ether. It still contains a small amount of the solvent in the crystal. When dried for several hours under reduced pressure at 80 C. it sinters and melts then at 134-136 C.

EXAMPLE 3 1- (ti-hydroxyethyl) -4- -tri-(4-chl0r0phenyl) propyl] -piperazine 55.2 grams of N-[7, ,7-tri-(4-chlorophenyl)-propyl]- N,N-bis-(fl-chloroethyl)-amine hydrochloride, 100 cc. of

separated is taken up in ethyl acetate, the latter is dried over magnesium sulfate and the solution is then concentrated to a volume of 100-150 cc. After cooling 26 cc. of alcoholic hydrochloric acid of 28% strength are added and, for completion of the crystallization, in addition 200 cc. of diisopropyl ether. There are obtained 39 grams of l-(fi hydroxyethyl) 4 tri-(4 chlorophenyl)- propylJ-piperazine dihydrochloride which can be recrystallized from 1 liter of isopropanol or from alcohol/ diisopropyl ether. The salt melts at 261-262 C. with decomposition.

By treating the dihydrochloride with dilute sodium hydroxide solution and ether, drying and evaporating the ether layer, there is obtained the free base as a light-yellow, very viscous oil.

EXAMPLE 4 1(0r 4-) methyl-1-(;8-hydroxyethyl) 4- -tri-(4- chlorophenyl) -prpyl] -piperazinium methyl sulfate To a solution of 29 grams of l-(p-hydroxyethyl)-4- -tri-(4-chlorophenyl)-propyl]-piperazine in 150 c-c. of benzene there is added dropwise a solution of 7.3 grams of dimethyl sulfate in 25 cc. of benzene. The reaction mixture is then heated for one hour under reflux. The solvent is distilled off and the residue is dissolved in 40 cc. of ethyl acetate. Upon prolonged standing crystallization sets in which can be accelerated by addition of inoculation crystalsJT'here are obtained 19 grams of l-(or 4-) methy 1 (5 hydroxyethyl) 4- tri (4 chlorophenyl)-propyl]-piperazinium methyl sulfate which can be recrystallized from ethyl acetate/diisopropyl ether and melts at 138-140 C.

EXAMPLE 5 1,1-dieIIIyl-4 -tri-4-chlorophenyI) -pr0pyl] piperazinium bicarbonate 55.2 grams of N-[ -tri(4-chlorophenyl)-proply]- N,N-bis-(fi-chloroethyl)-amine hydrochloride (prepared according to the directions given in Example 1), 300 cc. of alcohol and 22 grams of diethylamine are heated in an autoclave for 5 hours at 120 C. The solvent is then distilled off for the most part, the residue is poured into water and made strongly alkaline by means of sodium hydroxide solution. The solution obtained is extracted three times with ethyl acetate, the latter is dried over solid potassium hydroxide and, after filtering, carbon dioxide gas is introduced. The slight precipitate formed is filtered off. The ethyl acetate in the filtrate is distilled off for the most part and ether is added to the residue. After prolonged standing, more rapidly upon inoculation, the 1,1- diethyl 4 tri (4 chlorophenyl) propyl]- piperaziniurn bicarbonate crystallizes out. The yield amounts to 37 grams. The product can be recrystallized from ethyl acetate or acetonitrile. It melts at 148-150 C. with weak decomposition.

EXAMPLE 6 3 4ri- (4 -chl0r0phenyl -pr0py1 -3 ,6-diazaspiro- [5,5] -undecanium bicarbonate 55.2 grams of N-[ -tri-(4'-chlorophenyl)-propyl]- N,N-bis-(,8-choloethyl)-amine hydrochloride (obtained according to the directions given in Example 1), 300 cc. of alcohol and 26 grams of piperidine are heated in a shaking autoclave for 5 hours at l20-l30 C. The alcohol is distilled off, the residue is dissolved in a little water, the solution is made strongly alkaline by means of concentrated sodium hydroxide solution and extracted several times with ethyl acetate. The organic layer is dried over potassium hydroxide. A'fter separation of the drying agent, carbon dioxide gas is introduced into the solution obtained, the solution is concentrated to a small volume and about 1.5 liters of ether are added. The 3-[ -tri- (4' chlorophenyl) proply] 3,6 diaza spiro [5,5]- undecanium bicarbonate crystallizes rapidly and, after standing for several hours, it can be filtered off with suction. The slightly brownish product melts at 138-141 C. By recrystallization from dioxane ether and from acetonitrile it can be obtained in a colorless form, the melting point remaining constant.

EXAMPLE 7 3- [7,7,7-trf- (4-chl0r0phenyl)propyl] -9-meI/1yl-3,6,9- triaza-spiro- [5,5] -mzdecanium chloride A mixture of 55.2 grams of N tri (4 chlorophenyl) proply] N,N bis-fl-chloroethyDamine hydrochloride (obtained according to Example 1), 300 cc. of alcohol and 20 grams of N-methyl-piperazine are heated in a shaking autoclave for 5 hours at l20-l30 C. After cooling the precipitated product is filtered off with suction and the filtrate is evaporated. The residue and the sucked off substance are dissolved in water and made weakly alkaline by means of dilute sodium hydroxide solution. The solution is extracted four times with ethyl acetate, the combined extracts are dried over sodium sulfate and the solvent is completely distilled off. The residue is treated with a little acetone, whereupon the residue crystallizes. There are obtained 20 grams of 3-[ -tri- (4' chlorophenyl) propyl] 9 methyl 3,6,9 triazaspiro-[5,5]-undecanium chloride melting at 267-270 C. (The darkening commences at about 220 C.) The product can be recrystallized from acetonitrile. The melting tal water.

96 grams of 'y;y,'y-tri-(4-chlorophenyl)propylarnine, 47.3 grams of methyl-bis-(B-chloroethyl)-amine hydrochloride, 50 grams of triethylamine and 200 cc. of alcohol are heated in an autoclave for 5 hours at 120-130 C. Water is added to the reaction mixture which is then made alkaline by means of sodium hydroxide solution and the oil that has separated is taken up in ether. After drying and evaporating the organic layer there is obtained an oil which is dissolved in ether. A small excess of alcoholic hydrochloric acid is added thereto. After standing for several hours 15 grams of 1-methyl-4-['y,'y,- -tri- (4 chlorophenyl) propyl] piperazine dihydrochloride crystallize out which can be dissolved and reprecipitated from isopropanol/ether. The product melts then at 249-250 C. with slight decomposition.

The free base can be obtained from the salt in usual manner; it constitutes a yellow, very viscous oil.

EXAMPLE 9 52.5 grams of N-[B(3,4-dichlorobenzyl)'y-(3,4-dichlorophenyl)-propyl]-N,N-bis-(,8-chloroethyl) amine hydrochloride, 70 cc. of alcoholic ethylamine solution of 21.6% strength and 80 cc. of alcohol are heated in a shaking autoclave for 5 hours at 120-140 C. The alcohol is distilled off to a great extent, the residue is shaken with dilute sodium hydroxide solution and ether, the ether layer is separated, dried over magnesium sulfate and evaporated. The oily residue (41 grams) is dissolved in 250 cc. of ether and a small excess of alcoholic hydrochloric acid is added. The precipitated salt solidifies slowly and can then be filtered olf with suction. There are obtained 46 grams of 1 ethyl 4-[fl-(3,4-dichlorobenzyl)-v-3,-4'-dichlorophenyl)-propyl]-piperazine dihydrochloride which can be recrystallized from isoamyl alcohol and'nielts then at 251-253 C.

From the dihydrochloride the free base can be obtained in usual manner. It constitutes a light yellow, very viscous oil. The N-[fl-(3,4-dichlorobenzyl)-'y-(3,4-dichlorophenyl)-propyl] -N,N-bis-(fl-ch1oroethyl) -arnine hydrochloride serving as starting substance can, for example,

. be prepared as follows:

' 60 cc. of ethylene oxide are added and the reaction mixture is heated in the autoclave for 5 hours at 120 C. After distilling ofr the solvent under reduced pressure there remain behind 167 grams of crude N-[B-(3,4-dichlorobenzyl) -y- (3 ,4-dichloropheny1) -propyl] N,N-bis- (B-hydroxyethyD-amine as a very viscous, brownish oil which can further be reacted without purification.

The hydrochloride crystallizes from isopropanol/diisopropyl ether and melts at 116-118 C.

107 grams of crude N-[ti-(3,4-dichlorobenzyl) y-(3,4- dichlorophenyl -propyl] -N,N-bis- (e-hydroxyethyl) -amine are dissolved in 250 cc of chloroform. While slightly cooling there are added dropwise, at 20-30 C., 107 grams of thionyl chloride. After heating for one hour under reflux, chloroform and the thionyl chloride in excess are distilled off and the oil that remains behind is dissolved in 100 cc. of benzene. Crystallization sets in which is completed by addition of 500 cc. of diisopropyl ether. After filtering with suction there are obtained 112 grams of N [,8 (3,4 dichlorobenzyl)-'y-(3,4-dichlorophenyl)-propyl]-N,N-bis-(,Bchloroethy1) amine hydrochloride melting at 130-132 C. The degree of purity of this product suffices for the further working up. It can be .recrystallized from isopropanol/diisopropyl ether and melts then at 133-135 C.

EXAMPLE 10 1,1-diethyl-4- [fl-(3'4'-dichl0r0benzyl) -'y- (3,4-dichl0rophenyl)-propyl]piperazinium chloride A mixture of 40 grams of N-[/3-(3,4-dichlorobenzyl)- y-(3,4-diehlorophenyl)-propyl]-N,'N-bis (,B-chloroethyl) amine hydrochloride, 18.4 grams of diethylamine and 250 cc. of alcohol are heated in an autoclave for 5 hours at -130 C. The alcohol is distilled off for the most part, the residue is poured into Water, the reaction mixture is made distinctly alkaline by means of sodium hydroxide solution and extracted several times with chloroform. The combined extracts are dried over magnesium sulfate and the solvent is distilled off. The oil remaining behind is treated on the steam bath with 100 cc. of ethyl acetate, whereupon it crystallizes. 100 cc. of diisopropyl ether are added, the whole is cooled and filtered with suction. There are obtained 30 grams of 1,1-diethyl-4-[fi-(3',4-dichlorobenzyl)'y-(3,4'-dichlorophenyl) propyl] piperazinium chloride which can be recrystallized from isopropanol/ diisopropyl ether. The salt contains one molecular proportion of water of crystallization. It melts at 191192 C. with decomposition.

EXAMPLE 1 1 3 8 (3,4' dichlorobenzyl)-'y-(3,4-dichl0rophenyl) propyl] 9 methyl 3,6,9 triaza-spiro [5,5] undecanium chloride A mixture of 34 grams of N-[fi-(SA-dichlorobenzyl)-'y- (3,4-dichlorophenyl) propyl] N,N-bis-(e-chloroethyl)- amine hydrochloride, 250 cc. of alcohol and 21 grams of N-methylpiperaziue are heated in a shaking autoclave for 5 hours at C. The alcohol is distilled off for the most part, the residue is dissolved in water and rendered distinctly alkaline by means of sodium hydroxide solution. The reaction solution is extracted several times with chloroform, the combined extracts are dried over magnesium sulfate and concentrated again. The residue obtained in the form of crystals is dissolved in cc. of isopropauol, clarified by means of animal charcoal and precipitated again by addition of 500 cc. of diisopropyl ether. There are obtained 30 grams of 3-[,8-(3',4-di- ChlO1Obe1'lZy1)-Y-(3 ,4'-dichlorophenyl) -propyl] -9-methyl- 3,6,9-triaza-spiro-[5,5]-undecanium chloride which can be further purified by recrystallization from acetonitrile and drying at 90 C. under reduced pressure. The practically colorless product melts at 234236 C. with darkening and contains one molecular proportion of water of crystallization.

EXAMPLE 12 1 ethyl 4 [p (4 chlorophenyl) 'y (2', 4'

dichlorophenyl) propyl] piperazine slight excess of alcoholic hydrochloric acid is added and the sale crystallizes out upon addition of about 750 cc. of diisopropyl ether. There are obtained 55 grams of 1- etliyl --4 [fi-(4'-ch.lorophenyl) y-(2,4'-dichlorophenyl)- propyl]-piperazine dihydrochloride which can further be purified by recrystallization from alcohol/diisopropyl ether. It melts at 246-248 C. with decomposition.

The free 1 ethyl-4-[p-(4'-chlorophenyl)-- -(2,4-dichlorophenyl)-propyl]-p perazine is obtained from the salt in usual manner as yellowish viscous oil.

The N [/3 (4-chlorophenyl)-' -(2,4-dichlorophenyl) propyl] N,N bis (fi-chloroethyD-amine hydrochloride serving as starting substance may, for example, be prepared as follows: 200 grams of B-(4-chlorophenyl)-' -(2, 4-dichloropheriyl)-propylamine are dissolved in 400 cc. of benzene and, after addition of 85 cc. of ethylene oxide, heated in an autoclave for 5 hours at 120 C. The solvent is then completely distilled off under reduced pressure. As residue there are obtained 251 grams of the crude N [,8 (4 chlorophenyl) 'y (2,4 dichlorophenyl)- propyl]-N,N-bis-(fi-hydroxy-ethyl)-arnine in the form of a very viscous, dark yellow oil which can be further worked up without purification.

250 grams of N-[ti-(4-chlorophenyl)-y-(2,4-dichlorophenyl) -propyl] -N,N-bis-(fi-hydroxyethyl) -amine are dissolved in 480 cc. of chloroform and 250 grams of thionyl chloride are added dropwise, while stirring, at 20 C. The reaction mixture is heated for one hour under reflux and thionyl chloride and chloroform in excess are finally distilled off. The residue is dissolved in 100 cc. of benzene and 3 liters of diisopropyl ether are then added. A dark oil separates that crystallizes slowly. After filtering with suction there are obtained 280 grams of a still light brown product which can be reacted without further purification. The N- [B- 4-chlorop-henyl) -'y- 2,4-dichlorophenyl propyl]-N,N-di-(fl-chloroethyl)-amine hydrochloride can be recrystallized from isopropanol/diisoproylether and melts than at 132133 C.

EXAMPLE 13 1 (0r 4-) methyl 1 ethyl 4 [/3-4'-chl0r0phenyl)-'y- To a solution of 21.4 grams of 1-ethyl-4-[l3-(4chlorophneyl) 'y (2',4'-dichlorophenyl)-propyl]-piperazine in 150 cc. of benzene there is added dropwise a solution of 6.6 grams of dimethyl "sulfate in 50 cc. of benzene and the reaction mixture is then stirred for 15 minutes at room temperature and for one hour at the boiling temperature. Two layers are formed. After distilling off the benzene the residue is dissolved in 75 cc. of ethyl acetate, from which the quarternary salt crystallizes slowly. There are obtained 24 grams of l-(or 4-) methyl-1-ethyl-4-[,8-(4'-chlorophenyl) y (2',4'di-chlorophenyl)-propyl]-piperazinium methyl sulfate. After recrystallization from acetone/diisopropyl ether it melts at 97102 C.

EXAMPLE 14 1 butyl 4 [ti-(4' chlorophenyl) 'y (2,4

dichlorophenyl propyl] -piperazine A mixture of 119 grams of N-[B-(4-chlorophenyD-y- (2,4 dichlorophenyl) propyl]-N,N-bis-(,8-chloroethyl) amine hydrochloride, 500 cc. of alcohol and 55 grams of n-butylarnine are heated in a shaking autoclave for 5 hours at 110120 C. After most of the alcohol has been distilled ofi, the residue is poured into water, the reaction mixture is rendered alkaline by means of sodium hydroxide solution and the oil that has separated is taken up in ether. To the ethereal solution dried over sodium sulfate a slight excess of alcoholic hydrochloric acid is added, whereupon the 1 butyl 4 [fi-(4-chlorophenyl)-'y-(2',4'-dichlorophenyl) propyl] piperazine dihydrochloride crystallizes out. After filtering with suction there are obtained 80 grams of the compound which can be purified by recrystallization from 600 cc. of alcohol. The salt melts at 5- 257 C. with decomposition.

The free base is obtained from the dihydrochloride in usual manner as a light-yellow, viscous oil.

EXAMPLE 15 1-(0r 4-) methyl-l-butyll- 8-(4'-chl0r0phenyl) -'y-(2,4'- dichlorophenyl)-pr0pyl]-piperazinimn methyl sulfate 26.5 grams of 1-butyl-4-[fi-(4-chlorophenyl)-'y-(2',4- dichlorophenyl)-propyl]-piperazine are dissolved in 100 cc. of benzene and a solution of 7.6 grams of dimethyl sulfate in 25 cc. of benzene is added dropwise. The reaction mixture is heated for one hour under reflux and the solvent is distilled off under reduced pressure. The residue is again dissolved in 50 cc. of benzene and 100 cc. of petroleum ether are added thereto. The quaternary salt separates as viscous mass which solidifies slowly. After dissolving and reprecipitating once more in the same man ner there are obtained 21 grams of l-(or 4-)methyl-lbutyl-4[/3-(4-chlorophenyl) 'y (2',4'-dichlorophenyl)- propyl]-piperazinium methyl sulfate melting at 108- 113 C.

EXAMPLE 16 95.2 grams of N-[fl (4-chlorophenyl)--, -(2,4-dichlorophenyl)-propyl] N,N-bis (li-chloroethyD-amine hydrochloride, 400 cc. of alcohol and 46.4 grams of diethylaminoethylamine are heated in an autoclave for 5 hours at l20-130 C. After distilling off the alcohol, water and dilute sodium hydroxide solution are added, the separated oil is taken up in ether and the ethereal solution is dried over potassium carbonate. After separation of the drying agent there are added to the solution cc. of alcoholic hydrochloric acid of 27.8% strength. The l-diethylaminoethyl-4-[p-(4'-chlorophenyl) y-(2,4'-dichlorophenyl)- propyl]-piperazine trihydrochloride precipitates at first in a smeary form which solidifies slowly and can then be filtered off with suction. The yield amounts to 98 grams. The salt can further be purified by recrystallization from alcohol/diisopropyl ether. It crystallizes with one molecular proportion of water of crystallization and melts at 225-227 C. with slight decomposition.

The free amine can be obtained from the trihydrochloride in usual manner as light yellow, viscous oil.

EXAMPLE l7 3 [/3 (4' chlorophenyl)-'y-(2,4' dichlorophcnynpropyl]-9 methyl 3,6,9 triaza-spfr0[5,5] undecanium chloride hydrochloride 47.6 grams of N-[B-(4-chlorophenyl)-' -(2,4- dichlorophenyl)-propyl]-N,N-bis(fi-chloroethyl) amine hydrochloride, 300 cc. of alcohol and 22 grams of N-methylpiperazine are heated in an autoclave for 5 hours at 120- 130 C. The alcohol is distilled off, the residue is dissolved in water, made alkaline by means of sodium carbonate solution and the excess of methyl-piperazine is extracted by means of ether. The aqueous phase is rendered strongly alkaline by addition of concentrated sodium hydroxide solution and extracted by shaking several times with chloroform. The combined extracts are dried over magnesium sulfate and 24 cc. of alcoholic hydrochloric acid of 31% strength are added thereto. The 3-[ 3-(4-chlorophenyl-3-(2'-4-dichlorophenyl) propyl]- 9-methyl-3,6,9-triaza-spiro-[5,5]-undecanium chloride hydrochloride separates at once in a solid form. After recrystallization from cc. of alcohol there are obtained 30 grams of the salt crystallizing with 2 molecular proportions of water. It melts at 274276C.

EXAMPLE 18 A mixture of 63 grams of B-(4-chlorophenyl)-'y-(2,4- dichlorophenyl)-propylamine, 38.5 grams of methyl-bis- (B-chloroethyD-amine hydrochloride, 44.4 grams of triethlamine and 200 cc. of ethanol is heated in an autoclave for 5 hours at -130" C. The reaction mixture is poured into water, rendered alkaline by means of sodium hydroxide solution, the oil that has separated is taken up in ethyl acetate and the solution is dried over potassium carbonate. The solution is completely evaporated under reduced pressure, the residue is dissolved in 500 cc. of

13 ethyl acetate and 55 cc. of alcoholic hydrochloric acid of 28% strength are added. There are obtained 30 grams of 1-1nethyl-4-[fl-(4'-chlorophenyl) 'y (2',4-dichlorophenyl)-propyl]-piperazine dihydrochloride which can be recrystallized from isoamyl alcohol. It melts at 267- 269 C.

EXAMPLE l9 1,1-diethyl-4[,8,B-bis-(4'-chlor0benzyl)-propyl1- piperazinium chloride A mixture of 23.5 grams of N-[ 8,fi-bis-(4'-chlorobenzyl)-propyl] N,N-bis-(fl-chloroethyl)-amine hydrochloride, 100 cc. of alcohol and 11 grams of diethylamine are heated in an autoclave for hours at 120-130" C. The solvent is distilled off. A little water is added to the residue, whereupon crystallization takes place. The mixture is filtered with suction and the still moist product is recrystallized from 35 cc. of acetonitrile which is finally admixed with 50 cc. of diisopropyl ether. There are obtained grams of 1,1 diethyl-MBA bis (4'-chlorohenzyl)-propyl]-piperazinium chloride which can further be purified by recrystallization from acetonitrile/diisopropyl ether. It turns brown at 210 C. and melts at 222- 224 C. with decomposition.

The N-[@fi-bis-(4'-chlorobenzyl)-propyl] N,N bis- (fi-chloroethyD-amine hydrochloride can, for example, be prepared as follows:

124 grams of /3,fl-bis-(4-chlor0benzyl) propylamine are dissolved in 250 cc. of benzene, and, after addition of 57 cc. of ethylene oxide, heated for 5 hours at 140 C. in an autoclave. The solvent is distilled off and the oil remaining behind is dissolved in 100-150 cc. of diisoproyl ether. On standing, crystallization sets in slowly and can be improved by addition of petroleum ether. After filtering with suction, 70 grams of N-[fl,fi-bis-(4-chlorobenzyl)-propyl]-N,N-bis (fl-hydroxyethyl) amine are obtained which can be recrystallized from diisopropyl ether and melt at 114-116 C.

To a solution of 32 grams of N-[;3,fi-bis-(4-chlorobenzyl)-proyl]-N,N-bis-(,B-hydroxyethyl)-amine in 70 cc. of chloroform there are added dropwise, while stirring, at 15-20 C., 39 grams of thionyl chloride. The reaction mixture is then heated for one hour under reflux. The solvent and the thionyl chloride in excess are distilled off, the residue is dissolved in 50 cc. of benzene and 500 cc. of ether are added. There are thus obtained 32 grams of N-[5,13-bis-(4-chlorobenzyl -propyl] -N,N-bis-( 2-chlor- 'ethyl)-amine hydrochloride. After recrystallization from ethyl acetate/diisopropyl ether the product melts at 163- 166 C. For further reactions the product may be used in its crude form.

EXAMPLE 2O 39.3 grams of N-[B-(ZA dichlorobenzyl)-'y-(2,4-dichlorophenyl)-propyl] N,N-bis (fi-chloroethyD-amine hydrochloride, 16.5 grams of diethylamine and 100 cc. of ethanol are heated in a closed vessel for 5 hours at 110-120 C. The alcohol is distilled oif, the residue is dissolved in water and, after addition of a little 2 N-sodium hydroxide solution, the solution is extracted by shaking with ether. The aqueous phase is then extracted several times by means of methylene chloride, the combined methylene chloride extracts are dried over magnesium sulfate and the solvent is evaporated. The viscous oil remaining behind is dissolved in 100cc. of acetonitrile. On slowly adding 500 cc. of diisopropyl ether there crystallizes 34 grams of 1,1-diethyl-4-[B-(2,4'-dichlorobenzyl)-' -(2',4'- dichlorophenyl)-propyl] -piperazinium chloride. The product can further be purified by recyrstallization from the same solvents. The salt contains 1 molecular proportion of water of crystallization. It melts at 130-131 C.

The N-[fl-(2.,4-dichlorobenzyl) -'y-(2,4-dichlorophenyl) propyl]-N,N-bis (fl-chloroethyl) amine hydrochloride used as starting substance can, for example, be prepared as follows:

183 grams of [3-(2,4-dichlorobenzyl)- -(2,4-dichlorophenyl)-propylamine and 81 cc. of ethylene oxide are dissolved in 500 cc. of benzene and are heated in an autoclave for 5 hours at 120 C. After distilling 01f the solvent there remains behind a viscous oil in which crystals are formed upon prolonged standing. The raw product is dissolved in diisopropyl ether. On inoculation there are obtained 162 grams of N-[fi-(2,4-dicl1lorobenzyl)-' -(2,4- dichlorophenyl)-propyl] N,N bis (fi-hydroxyethyl)- amine melting at 89-90 C. After recrystallization from isopropanol the hydrochloride melts at 155-156" C.

To a solution of 70 grams of N-[fl(2,4-dichlorobenzyl) -'y-(2,4-dichlorophenyl) -propyl] N,N-bis-(fl-hydroxyethyl)-amine in 130 cc. of chloroform there are added dropwise at 20 C., while stirring, 75 grams of thionyl chloride and the reaction mixture is heated for one hour under reflux. After distilling ofl? the solvent and the thionyl chloride in excess, the residue is dissolved in cc. of benzene and 1000 cc. of diethyl ether are added thereto. The precipitated N-[e-2,4-dichlorobenzyl)-'y-(2,4-dichlorophenyl) -pr0pyl] -N,N-bis- B-chloroethyl -amine hydrochloride crystallizes on rubbing. The yield amounts to 77 grams. The product thus obtained can be used directly for further reactions. After recrystallization from benzene it melts at 108-110 C.

EXAMPLE 21 1,1-diethyl-4 [fl-(3',4' dichl0r0phenyl)-'y-(4' chlorophenyl) -pr0pyl] -piperazinium chloride 47.6 grams of N-[,8-(3,4-dichlorophenyl)-'y-(4-chl0rophenyl)-propyl]-N,N-bis (B-chloroethyl) amine hydrochloride, 35.5 grams of diethylamine and 200 cc. of ethanol are heated in a closed vessel for 5 hours at 110- C. The alcohol is distilled off for the most part, the residue is dissolved in water, a small amount of 2 N- sodium hydroxide solution is added, the whole is extracted with ether and the aqueous phase is then extracted several times with methylene chloride. The combined methylene chloride extracts are dried over magnesium sulfate and evaporated. The oily residue crystallizes after some time on mixing with cc. of ethyl acetate. The crystallization can be accelerated by inoculation. There are obtained 25 grams of 1,1-diethyl-4-[B (3,4-dichlorophenyl)-'y-(4'-chlorophenyl) propyl]-piperazinium chloride which can further be purified by recrystallization from acetone/diisopropyl ether. The salt contains 2 molecular proportions of water of crystallization and melts at 88-90 C.

The N-[B-(3,4-dichlorophenyl)-y-(4 chlorophenyl)- propyl] N,N-bis-(fi-chloroethyl) amine hydrochloride can, for example, be prepared as follows:

150 grams of B-(3,4-dichlorophenyl)-'y-(4-chlorophen yl)-propylamine and 63 cc. of ethylene oxide are dissolved in 250 cc. of benzene and heated in a closed vessel for 5 hours at 110-120 C. After the solvent has been completely distilled off under reduced pressure there remain behind 197 grams of N-[5-(3,4-dichlorophenyl) y- (4-chlorophenyl) propyl] N,N-bis (,B-hydroxyethyD- amine as dark yellow, very viscous oil.

183 grams of N-[fl-(3,4-dichlorophenyl)-'y-(4-chlor0- pheny1)-propyl]-N,N-bis-(,B-hydroxyethyl) -amine are dissolved in 400 cc. of chloroform and 183 grams of thionyl chloride are added dropwise at 10-20 C. The reaction mixture is heated for one hour under reflux. The chloroform and the thionyl chloride in excess are completely distilled off. There is obtained the N-[B- (3,4-dichlorophenyl)-' -(4-chlorophenyl)-propyl]-N,N-bis (B chloroethyl)-amine hydrochloride as a dark, very viscous product which can be used in this form for further reactions.

15 EXAMPLE 22 1,1-diethyl-4-['y -bis-(4'-chl0r0phenyl)-pr0pyl]- piperazinium chloride 44.2 grams of N-['y,'y-bis-(4chlorophenyl)-propyl]-N, N-bis-(fi-chloroethyl)-amine hydrochloride and 35.5 grams of diethylamine are heated in 200 cc. of ethanol in a closed vessel for hours at 110120 C. The alcohol is distilled off and the product remaining behind is dissolved in water. After addition of a small amount of 2 N-sodium hydroxide solution the reaction mixture is shaken with ether and the aqueous phase is extracted several times with methylene chloride. After drying over magnesium sulfate and evaporation of the solvent, there is obtained from the combined methylene chloride extracts a viscous product which crystallizes after some time upon trituration with 100 cc. of acetone. (The crystallization sets in more rapidly by inoculation.) There are obtained 20 grams of 1,1-diethyl 4 ['y,'y-bis-(4'-Chlor0phenyl)- propyl]-piperaziniu-m chloride which can further be purified by recrystallization from acetonitrile/diisopropyl ether. The salt contains /2 molecular proportion of water of crystallization and melts at 2'O7208 C., with decomposition.

The N-[yq-bis-(4-chlorophenyl) propyl] N,N-bis- (B-chloroethyD-amine hydrochloride used as starting substance can, for example, be prepared as follows:

147 grams of 'y,'y-bis-(4-chlorophenyl) propylamine and 74 cc. of ethylene oxide are dissolved in 350 cc. of benzene and heated in an autoclave for 5 hours at 110-120'C. After distilling off the solvent under reduced pressure there remain 195 grams of N['y,'y-biS-(4-chlOrO- phenyl -propyl] -N,N-bis-( [i -hydroxyethyl -amine in the form of a dark yellow, very viscous oil.

vTo a solution of 192 grams of N-[yq-bis-(4-Chl0r0- phenyl)-propyl]-N,N bis-(/8-hydroxyethyl)-amine in 400 cc. of chloroform there are added dropwise at 10-20 C. 235 grams of thionyl chloride and the reaction mixture is heated for one hour under reflux. After distilling off the solvent and the chlorination agent in excess, the residue is dissolved in 200 cc. of ethyl acetate. By addition of 750 cc. of ether and some inoculation crystals there are obtained 139 grams of N-[yq-bis-(4-chlorophenyl)- propyl] -N,N-bis-(.,6-chl0roethyl)-amine hydrochloride as 'light brown powder which can be reacted without further purification. The compound can further be purified by recrystallization from ethyl acetate/diisopropyl ether and melts then at 15816'1 C.

We claim: 1. A compound of the formula R. R Rz-( l-CH2N N-R4 t. l

1 6 physiologically compatible acid addition salts thereof, or quaternary salts thereof in which the cations are of the formulas wherein R is hydrogen, halophenyl or halobenzyl; R R and R are hydrogen or halophenyl, at least two of R R and R being halophenyl when R is hydrogen and at least one of R R and R being halophenyl when R is halophenyl or halobenzyl; A is hydrogen or lower alkyl; R; is hydrogen, alkyl of l-4 carbon atoms, hydroxyalkyl of l-4 carbon atoms or dialkylaminoalkyl, the alkyl groups of which have l-4 carbon atoms; R is hydrogen or alkyl of 1-4 carbon atoms; or R and R together with the nitrogen atom form a piperidino or N-methylpiperazino ring.

2. A 1,1-diethyl-4-[fi (3,4'-dichlorobenzyl)-'y-(3,4'- dichlorophenyl)-propyl] pipe-razinium salt of a physiologically compatible acid.

3. A 1,1- dimethyl-4-[fi-(2,4-dich1orobenzyl)-'y-2',4- dichlorophenyl)-propyl] piperazinium salt of a physiologically oompatible acid.

4. A 1,l-diethyl-4-[' qn -tri-(4-chlorophenyl)-propyl] piperazinium salt of a physiologically compatible acid.

5. A physiologically compatible acid addition salt of 1-methyl-4-[,B-(4-chlorophenyl) 'y (2',4-dichlorophenyl)-propyl]-piperazine.

6. N rnethyl-N"-[B-(3,4 (liClllOlObCl'tZYl)-'y-(3',4'- dichlorophenyl)-propyl]-N-spirodipiperazinium chloride.

References Cited UNITED STATES PATENTS 2,767,186 10/1956 Baltzly et al 260268 ALEX MAZEL, Primary Examiner.

HENRY R. JILES, Examiner.

JAMES W. ADAMS, JR., Assistant Examiner. 

1. A COMPOUND OF THE FORMULA 